Hypertrophic cardiomyopathy (HCM) is the most common heart disease in cats and the most common cause of heart failure in this species (Riesen et al., 2007; Rush et al., 1998). While a genetic mutation of one or more of the sarcomeric proteins has been proposed to be the cause of HCM in most cats, a specific mutation has only been identified for Maine coon and Ragdoll cats (Meurs et al., 2005 and 2007; Kittleson et al., 1999). In most cats identified to have HCM, the heart disease is the eventual cause for death. HCM together with restrictive cardiomyopathy (RCM) are classified as diasystolic dysfunctions.
Five common phenotypical manifestations of feline HCM include 1) diffuse, symmetric concentric hypertrophy of the left ventricle (LV); 2) asymmetric hypertrophy of the interventricular septum (IVS) with a normal LV free wall, such that the IVS impinges into the left ventricular outflow tract during systole; 3) asymmetric hypertrophy of the left ventricular free wall (with normal thickness of the IVS); 4) mid-ventricular hypertrophy of the left ventricle with sparing of the cardiac base and the apex causing mid-ventricular obstruction; and 5) isolated papillary muscle hypertrophy most often seen in Maine Coon cats (Peterson et al., 1993; Fox 2003; Liu et al., 1993; Kittleson et al., 1999).
Treatment of symptoms of HCM is directed towards decreasing the left ventricular outflow tract gradient and symptoms of dyspnea, chest pain and syncope. Medical therapy is successful in the majority of patients. The first medication that is routinely used is a β-blocker (metopolol, atenolol, bisoprolol, propranolol). If symptoms and gradient persist, disopyramide may be added to the β-blockers. Alternately a calcium channel blocker such as verapamil may be substituted for a beta blocker.
Restrictive cardiomyopathy (RCM) is a form of cardiomyopathy in which the walls are rigid, and the heart is restricted from stretching and filling with blood properly. Rhythmicity and contractility of the heart may be normal, but the stiff walls of the heart chambers (atria and ventricles) keep them from adequately filling, reducing preload and end-diastolic volume. So blood flow is reduced, and blood that would normally enter the heart is backed up in the circulatory system. In time, restrictive cardiomyopathy patients develop diastolic dysfunction and eventually heart failure.
PDE III Inhibitors and Ca2+-sensitizing agents such a pimobendan or levosimendan are well-known compounds for the treatment of heart failure (HF) originating from dilated cardiomyopathy (DCM) or decompensated endocardiosis (DCE) in animals, especially for the treatment of dogs suffering from heart failure (see for example WO 2005/092343). PDE-III inhibitors including those having Ca2+-sensitizing effects and Ca2+-sensitizing agents are known to be inotropic and may increase the contractility of the left ventricle. Therefore, it was believed that use of PDE III inhibitors including those having Ca2+-sensitizing effects and Ca2+-sensitizing agents are contraindicated for the treatment of HCM.
Concentric hypertrophy of the left ventricle results in a reduced left ventricular internal dimension and slowed ventricular relaxation, and consequently impedes diastolic filling. Altered diastolic filling and compromised myocardial blood flow result in myocardial ischemia and, as a consequence of ischemia, a progressive loss of cardiomyocytes. Over time, the heart becomes stiff and non-compliant and the hypertrophied muscle is replaced with fibrous tissue which further impedes diastolic filling. PDE-III Inhibitors by inhibiting the breakdown of the second messenger of catecholamines (increase in cytosolic cAMP and Ca2+ due to inhibition of PDE-III) and increasing the sensitivity of the contractile proteins towards Ca2+ would be expected to further impair diastolic ventricular function, when administered to those patients. Moreover, enhancing systolic function would lead to further increase of the left ventricular (LV) wall, especially in those segments, where the pathoanatomical changes have resulted in obstruction of the left ventricular outflow and would thus further deteriorate left ventricular pump function. Evidence for the latter hypothesis is given by clinical observations that can be made especially under the influence of stress, which is frequently induced by clinical examination of cats: As the cat becomes excited, the murmur increases in intensity as a result of increased heart rate, increased systolic inotropic state, and increased velocity of blood flow in the LV outflow tract, and the resulting mitral regurgitation. The LV outflow tract obstruction, due either to systolic bulging of the bicuspid valve or hypertrophy at the top of the interventricular septum, may lead to increased systolic wall stress, increased myocardial oxygen demand with demand-supply mismatch, worsening of LV hypertrophy, acceleration of diastolic dysfunction, arrhythmias, and finally disease progression over time. This is one of the reasons that many clinicians prescribe bradycardic agents to keep the heart rate slow and blunt this dynamic worsening of the left ventricular outflow tract obstruction. Moreover, Tilley and co-workers demonstrated the deleterious rise in left ventricular end diastolic pressures which results from sympathetic stimulation in 19 cats with HCM (Tilley et al., 1977). This sudden rise in LV end diastolic pressure results in elevated left atrial pressure and subsequent acute pulmonary edema. This model, which used isoproterenol infusion, is thought to mimic the rise in sympathetic tone associated with stressful events in cats which can lead to an abrupt onset of pulmonary edema in a previously well-compensated animal.
The problem underlying the present invention was to provide a medication, which allows the treatment of diastolic dysfunction, preferably HCM and to reduce the risk of death in patients with heart failure associated with diastolic dysfunction, in particular with HCM. In particular, the problem underlying the present invention was to provide a medication which allows the treatment of HCM in patients suffering from heart failure.